Novel Biodegradable Protonic Ionic Liquid for the Fischer Indole Synthesis Reaction

Home , Fischer indole synthesis

Rowan University Rowan Digital Works

Faculty Scholarship for the College of Science & Mathematics College of Science & Mathematics

3-9-2016

Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction

William C. Neuhaus

Ian J. Bakanas

Joseph R. Lizza

Charles T. Boon Jr.

Gustavo Moura-Letts Rowan University, [email protected]

Follow this and additional works at: https://rdw.rowan.edu/csm_facpub

Part of the Organic Chemistry Commons

Recommended Citation Neuhaus, W. C., Bakanas, I. J., Lizza, J. R., Boon, C. T., & Moura-Letts, G. (2016). Novel biodegradable protonic ionic liquid for the fischer indole synthesis eaction.r Green Chemistry Letters and Reviews, 9(1), 39-43.

This Article is brought to you for free and open access by the College of Science & Mathematics at Rowan Digital Works. It has been accepted for inclusion in Faculty Scholarship for the College of Science & Mathematics by an authorized administrator of Rowan Digital Works. Green Chemistry Letters and Reviews

ISSN: 1751-8253 (Print) 1751-7192 (Online) Journal homepage: http://www.tandfonline.com/loi/tgcl20

Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction

William C. Neuhaus, Ian J. Bakanas, Joseph R. Lizza, Charles T. Boon , Jr. & Gustavo Moura-Letts

To cite this article: William C. Neuhaus, Ian J. Bakanas, Joseph R. Lizza, Charles T. Boon , Jr. & Gustavo Moura-Letts (2016) Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction, Green Chemistry Letters and Reviews, 9:1, 39-43, DOI: 10.1080/17518253.2016.1149231 To link to this article: http://dx.doi.org/10.1080/17518253.2016.1149231

Published online: 09 Mar 2016. Submit your article to this journal

Article views: 466 View related articles

View Crossmark data Citing articles: 5 View citing articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=tgcl20

Download by: [Rowan University] Date: 01 March 2017, At: 12:58 GREEN CHEMISTRY LETTERS AND REVIEWS, 2016 VOL. 9, NO. 1, 39–43 http://dx.doi.org/10.1080/17518253.2016.1149231

LETTER Novel biodegradable protonic ionic liquid for the Fischer indole synthesis reaction William C. Neuhausa, Ian J. Bakanasa, Joseph R. Lizzaa, Charles T. Boon, Jr.b and Gustavo Moura-Lettsa aDepartment of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, USA; bDepartment of Chemical Engineering, Rowan University, Glassboro, NJ, USA

ABSTRACT ARTICLE HISTORY Novel eco-friendly tetramethylguanidinium propanesulfonic acid triﬂuoromethylacetate ([TMGHPS] Received 6 October 2015 [TFA]) ionic liquid was developed as catalyst and medium for the Fischer indole synthesis of a wide Accepted 28 January 2016 variety of hydrazines and ketones. The indole products were isolated in high yields and with KEYWORDS minimal amounts of organic solvent. This reaction showed that [TMGHPS][TFA] can be Ionic liquids; indole; Fischer regenerated and reused with reproducible yields without eroding the integrity of the ionic liquid. indole synthesis; tetramethylguanidinium; biodegradable

Introduction Acid-promoted organic reactions are among the most molecules with pharmacological properties (12). Their important transformations in the chemical industry (1). synthesis has been a major focus in the ﬁeld of organic Brønsted acid catalyst has recently taken a more relevant chemistry for over 100 years, and a variety of methods role with the introduction of organocatalysis (2). are available for their synthesis (13–15). The reaction of

However, the use of these conventional methods hydrazines and ketones to make indoles (Fischer indole suffers from low solubility, waste production, corrosive- synthesis) still remains one of the most reliable ness, recycling, and high volatility (3). Ionic liquids (ILs) approaches for the synthesis of these scaffolds (16–18). have been widely utilized as solvents for a range of Despite being largely investigated, Lewis acids (ZnCl2, organic reactions with the potential of improving TiCl4), Brønsted acid catalysts (H2SO4, HCl, PPA, AcOH, product distribution, recycling, reaction rates, and reac- TsOH), and solid acids (zeolite, rutile) have proven to tion chemo-, regio-, and stereoselectivities (4, 5). More- be the simplest and most effective promoters for this over, reactions in ILs remove the risks of fugitive transformation (19,20). emissions and combustion of conventional small However, the development of innovative, environ- organic molecules widely used as solvents in organic mentally benign and cost-efficient catalysts and catalytic reactions (6, 7). systems remains a main objective in the field of organic Biodegradable ILs offer a greener alternative to tra- chemistry. ditional Brønsted–Lewis acid catalyst with the potential ILs have been previously used to promote the Fischer to further increase the efficiencies of organic transform- indole synthesis with a variety of results and efficiencies ation (8). Protonic ILs have been reported as a new class (21). Pyridinium and choline ILs have been shown to of promising compounds for the development of promote the reaction with good efficiencies, but the cat- environmentally friendly acidic catalysts owing to their alysts’ lack of stability limited their application (22). combined advantages as both liquid acids and ILs. Pd- Similar efforts have shown that highly stable Brønsted promoted coupling reactions with guanidine and acid imidazolium IL ([bmim][HSO4]) promote this reac- amino acid-based ILs are among the most successful tion with good conversions but with limited scope (23). examples (9–11). Xu et al. demonstrated that increasing the acidity of

The indole molecular framework is among the most the IL by introducing an alkyl-SO3H group, largely recurrent heterocyclic structure in natural and synthetic increased the scope and efﬁciencies of the reaction (24).

CONTACT Gustavo Moura-Letts [email protected] Supplemental data for this article can be accessed at the Taylor & Francis website, doi:10.1080/17518253.2016.1149231 © 2016 The Author(s). Published by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 40 W.C.NEUHAUSETAL.

complete conversion (Scheme 1). Upon the successful synthesis of these ILs, we began to study their ability to promote the Fischer indole synthesis. The formation of Scheme 1. Synthesis of novel protonic TMG ILs. indoles by reacting hydrazines and ketones goes through an initial formation of hydrazone intermediate 3, which then undergoes a [3,3]-sigmatropic rearrange- Table 1. Indole synthesis with 2-trifluoromethylhydrazine and ment followed by loss of ammonia to form indole 4 cyclohexanone with different protonic ILs. (Table 1). Based on the demonstrated promoting ability of similar ILs (27), deactivated hydrazine (2-trifluoromethylhydrazine) and cyclohexanone were used as the model reaction substrates for these ILs. [TMGH][lactate] was hypothesized as a potential promoter of this reaction (Table 1). Unfortunately, we were only able to a b Entry IL Conversion Yield 3 Yield 4 obtain hydrazone 3 from the reaction crude (Entry 1). 1 [TMGH]lactate 90% 90% 0% The key [3,3]-sigmatropic rearrangement requires 2 [TMGH]phthalate >95% 88% 8% 3 [TMGH]succinate >95% 78% 20% strong acidic conditions; so we rationalized that ILs 1a- 4 [TMGH]malonate >95% 95% 3% d would be better candidates for this reaction. Unfortu- 5 [TMGH]maleate >95% 93% 3% nately, we found that phthalate 1a and succinate 1b 6CF3CO2H >99% 99% 0% 7 TMG 0% 0% 0% (Entries 2 and 3) did form indole 4, but in poor yields 8 Sultone 0% 0% 0% 8% and 20%, respectively. Malonate 1c and maleate 1d 9 [TMGHPS]NO3 >99% 50% 50% 10 [TMGHPS]OAc >99% 35% 62% only provided indole 4 in trace amounts (Entries 4 and 5). 11 [TMGHPS]Cl >99% 15% 82% It has been reported that imidazolium salts react at RT 12 [TMGHPS]HSO4 >99% 16% 84% 13 [TMGHPS]TFA >99% 3% 97% with sultones to provide the respective alkylated imida- 14 [TMGHPS]OTf >99% 20% 60% zolium sulfonic acid (28). Consequently, we reacted Note: Reaction conditions: Hydrazine (1 mmol), ketone (1 mmol), and IL (1 TMG with 1,3-propane sultone, and we were pleased to mmol) were mixed and heated to 90°C. aReaction conversion measured by 1H-NMR. find that TMGH sulfonate was obtained with complete b

Isolated yield. conversion (Scheme 2). This intermediate compound was then poised to react with a variety of inorganic Tetramethylguanidine (TMG) ILs have been utilized to and organic acids to form the respective ILs 2a-f. These promote a variety of organic reactions (25). Among these, were water stable, non-volatile, and non-miscible with [TMGH][lactate] has received considerable attention for organic solvents and were all obtained with complete its green and biodegradable properties, and for its effi- conversion. cient promotion of important organic transformations With these in hand, we went ahead and test their ability (26). We propose a novel class of eco-friendly TMG- to promote the indole reaction (Table 1). We found that based ILs with an alkyl acid substituent for the efficient the nitrate 1a and acetate 1b ILs (Entries 9 and 10) radi- Fischer indole synthesis. To the best of our knowledge, cally improved the formation of indole 4 (50% and 60% this is the first time TMG-based ILs have been applied respectively). Furthermore, chloride 1c and bisulfate 1d to the synthesis of complex heterocyclic scaffolds. provided the indole in synthetically useful yields (Entries 11 and 12, 82% and 84% yield, respectively). We then decided to use a stronger acid and we found that trifluor- oacetate 1e provided indole 4 in 97% yield (Entry 13). Results and discussion Conversely, triflate 1f provided the indole 4 in consider- We hypothesized whether a greener [TMGHCOOH]car- ably lower yield (Entry 14, 60% yield). We were enthusias- boxylate would efficiently promote the Fischer indole tic to find that tetramethylguanidinium propanesulfonic synthesis reaction. Thus, we reacted neat TMG with a acid trifluoromethylacetate ([TMGHPS][TFA]) was the series of organic dicarboxylic acids to furnish 1a-d with ideal protonic IL for this reaction. We verified that the

Scheme 2. Synthesis of novel protonic TMG sulfonic acid ILs. GREEN CHEMISTRY LETTERS AND REVIEWS 41

Fischer indole reaction was indeed being promoted in the Table 2. Fischer indole synthesis scope for presence of this IL by exposing the reaction to just trifluor- activated and deactivated hydrazines, and oacetic acid and we found only complete conversion to symmetric and nonsymmetrical ketones. hydrazone 3 (Entry 6, 99% yield). Moreover, TMG or sultone alone only provided the unreacted starting material (Entries 7 and 8). Having established [TMGHPS][TFA] as the ideal IL for this transformation, we focused on assessing the scope of this reaction using this IL for a variety of ketones and hydrazines (Table 2). We assessed a variety of activated and deactivated hydrazines to establish the scope of [TMGHPS][TFA] 2e. Activated hydrazines (4- methyl, 4-methoxy, and phenyl) with cyclohexanone in the presence of 2e provided the respective indoles in very good yields (Entries 1, 2 and 3). Similarly, deactivated hydrazines (2-bromo, 4-chloro, 4-fluoro and 2-tri- fluoromethyl) provided the expected indoles in excellent yields (Entries 4, 5, 6 and 7). These initial results demonstrated that 2e was promoting this reaction with good generality. However, highly deactivated hydrazines (4-nitro, 2,4-dinitro and 4-cyano) provided mostly complex mixtures with predo- minant formation of the hydrazone intermediate. We then focused on the indole synthesis of other ketones. 4-Methylcyclohexanone successfully provided the indoles in similar yields as in the cyclohexanone series

(Entries 8–12). Deactivated 2-Trifuoromethylhydrazine and 4-methylcyclohexanone reacted with high conversion, but the isolated yield was slightly lower than expected (Entry 13, 68% yield). Encouraged by these results, we tried the reaction with unsymmetrical ketones. We found that 2-octanone with 4-chloro and 2-triﬂuoro hydrazines selectively provided the respective indoles in good yields (Entries 14 and 15, 71% and 66% yield, respectively). The regioselec- tivity of the indole synthesis with 2-octanone was shown to have complete selectivity for the 2-methyl indole isomer. Moreover, the reactions with methyl ethyl ketone with 4-methoxy and 4-chloro hydrazines were also successful at providing the thermodynamically favored indole in good yields (Entries 16 and 17 with 93% and 71% yield, respectively). We were also inter- ested in assessing the reactivity with 3-pentanone and we found that when reacting with 4-methoxy, 4-chloro and 2-bromo hydrazines, the indoles were obtained in very high yields as well (Entries 18, 19 and 20 with 91%, 93% and 95% yield, respectively). Analogously to 2-octanone, the 2-methyl indole regioisomer was made selectively. We further investigated the scope of 2e, and found that sterically demanding ketones (acetophe- aReaction conversion was measured by 1H-NMR. b none, 1-tetralone) do not form the desired indole. Isolated yields. 42 W.C.NEUHAUSETAL.

Table 3. Indoles from 7-methoxy-2-tetralones toward 4-chloro and 2-bromo reacted to provide the expected alkaloid core. indole in good yields (Entries 3 and 4, 79% and 75% yield). We then focused our efforts on determining the recyclability of our protonic IL 2e (Table 4). Due to the fact that the reaction was performed in the presence of water, IL 2e had the potential to be recycled by simple extraction of the organic product. More- over, exposing the aqueous solution to trifluoroacetic acid acidified the recovered IL. We decided to use 2- trifluoromethylhydrazine and cyclohexanone as our model example. We were able to use IL 2e through eight Fischer indole synthesis reaction cycles with complete conversion to indole 4 in each cycle. After cycle 4 we began to see erosion of 2e, and by cycle 9 the reaction conversion dropped to 40% yield of 4. The IL could be further purified by multiple extrac-

tions with EtOAc/CHCl3 mixtures to regenerate its activity. However, the overall recovery of 2e was limited to 50% yield. aReaction conversion was measured by 1H-NMR. bIsolated yields. Conclusions We have demonstrated that [TMGHPS][TFA] 2e can Biologically relevant alkaloids share the indole 5 mol- efﬁciently promote Fischer indole synthesis reactions ecular scaffold as their phamacophore core (Table 3). for a wide variety of activated and deactivated hydra- We believe we could access these important synthons zines and symmetrical and nonsymmetrical ketones. by the Fischer indole synthesis of hydrazines and substi- We established that 2e was the optimal promoter for tuted 2-tetralones. We reacted 7-methoxy-2-tetralone the indole synthesis of activated and deactivated with activated 4-methoxyhydrazine and we found that hydrazines. Moreover, we were able to apply this pro- we were able to reach almost complete conversion tocol to the synthesis of alkaloids indole core by react- after 12 h (Entry 1). Moreover, we were able to isolate ing hydrazines with 7-methoxy-2-tetralone. We were the desired indole in 73% yield. We then reacted 2-tri- also able to demonstrate that [TMGHPS][TFA] can be ﬂuoromethyl and found that we were also able to recycled and reused for up to 8 cycles with reproduci- obtain the desired indole (Entry 2, 64% yield). Similarly, ble conversions and yields.

Table 4. Fischer indole synthesis reaction with [TMGHPS][TFA] recycling study.

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Conversiona 100% 100% 100% 100% 100% 100% 95% 95% 65% 50% Yield of 4b 97% 96% 97% 98% 95% 96% 92% 91% 40% 20% Purity of ILc 100% 100% 100% 100% 95% 90% 89% 86% 75% 50% Timed 60 min 60 min 60 min 60 min 80 min 90 min 90 min 120 min 180 min 240 min aReaction conversion was measured by 1H-NMR. bIsolated yields. cIL purity was measured by 1H-NMR. dReaction was monitored by TLC. GREEN CHEMISTRY LETTERS AND REVIEWS 43

Experimental ORCID Synthesis of [TMGHPS][TFA] 2e: In a 30 mL round-bot- Gustavo Moura-Letts http://orcid.org/0000-0001-8156- tomed ﬂask 1,1,3,3-tetramethylguanidine (1.50 mL, 12 151X mmol, 1 equiv.) was cooled to 0°C and 1,3-propanesul- tone (1.05 mL, 12 mmol, 1 equiv.) was then added. The References resulting mixture was stirred at 0°C for 30 min and (1) Arpe, H.J. Industrial Organic Chemistry, 5th ed.; Wiley-VCH: then 5 mL of DI water were added. The resulting Weinheim, 2010. mixture was then treated with triﬂuoroacetic acid (918 (2) James, T.; Van Gemmeren, M.; List, B. Chem. Rev. 2015, 115, – μL, 12 mmol, 1 equiv.) and then heated to 90°C for 12 9388 9409. (3) Ranu, B.C.; Banerjee, S. Org. Letters. 2005, 7, 3049–3052. h. The resulting mixture was then diluted with DI water (4) Poliakoff, M.; Fitzpatrick, J.M.; Farren, T.R.; Anastas, P.T. to make a 1 M solution. IL was fully characterized after Science. 2002, 297, 807–810. removal of excess water under vacuum to afford neat (5) Sheldon, R.A.; Arends, I.W.C.E.; Henefeld, U. Green Chemistry 2e as a clear liquid (3.41 mL, 99% yield). 1H NMR (400 and Catalysis, 1st ed.; Wiley-VCH: Weinheim, 2007. MHz, D O) δ 3.54 (t, J = 6.6 Hz, 2H), 2.82 (s, 12H), 2.79 (6) Hallett, J.P.; Welton, T. Chem. Rev. 2011, 111, 3508–3576. 2 – (t, J = 6.4 Hz, 2H), 1.81 (quintet, J = 6.6 Hz, 2H). 13C-NMR (7) Kulpa, C.F.; Docherty, K.M. Green Chem. 2005, 7, 185 190. δ (8) Garcia, M.T.; Gathergood, N.; Scammells, P.J. Green Chem. (125 MHz, D2O): 163.5, 161.4, 118, 60.2, 48.2, 38.5 2005, 7,9–14. (4C), 27.3 ppm. ESI–MS m/z (rel int): (pos) 238.11 ([M- (9) Binnemans, K. Chem. Rev. 2005, 105, 4148–4204. TFA]+, 100). (10) Ohno,H.; Fukumoto,K.Acc. Chem.Res. 2007, 40,1122–1129. General protocol for the Fischer indole synthesis:Ina4 (11) Li, S.; Lin, Y.; Xie, H.; Zhang, S.; Xu, J. Org. Lett. 2006, 8,391– 394. mL vial 0.5 mL of a 1M [TMGHPS][TFA] in H2O was mixed (12) Shiri, M. Chem. Rev. 2012, 112, 3508–3549. with hydrazine (0.1 mmol, 1 equiv.) and ketone (0.1 (13) Key reviews: Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, mmol, 1 equiv.). The resulting mixture was heated at 2873–2920. 90°C for 30 min or until the reaction was completed by (14) Humphrey, G.R.; Kuethe, J.T. Chem. Rev. 2006, 106, 2875– thin layer chromatography (TLC). The mixture was then 2911. extracted with Diethyl Ether and the combined organic (15) Kruger, K.; Tillack, J.T.; Beller, M. Adv. Synth. Catal. 2008, – layers were concentrated under reduced pressure. The 350, 2153 2167.

fl fi (16) Chen, H.; Eberlin, L.S.; Ne iu, M.; Augusti, R.; Cooks, R.G. resulting crude was then quickly puri ed by automated Angew. Chem. Int. Ed. 2008, 47, 3422–3425. silica gel chromatography using combinations of hep- (17) Schmidt, A.M.; Eilbracht, P. J. Org. Chem. 2005, 70, 5528–5535. tanes and EtOAc. (18) Benjamin, A.H.; Zhang, Z.-G.; Li, J.-S.; Knochel, P. Angew. Chem. Int. Ed. 2010, 49, 9513–9516. (19) Liu, K.G.; Robichaud, A.J.; Lo, J.R.; Mattes, J.F.; Cai, Y. Org. Letters. 2006, 8, 5769–5771. Acknowledgements (20) Lipiska, T.M.; Czarnocki, S.J. Org. Letters. 2006, 8, 367–370. (21) Li, B.L.; Xu, D.Q.; Zhong, A.G. J. Fluorine Chem. 2012, 144,45–50. We would like to thank the Department of Chemistry and Bio- (22) Morales, R.C.; Tambyrajah, V.; Jenkins, P.R.; Davies, D.L.; chemistry and the College of Science and Mathematics at Abbott, A.P. Chem. Commun. 2004, 40, 158–159. Rowan University for the institutional support. (23) Xu, D.-Q.; Yang, W.-L.; Luo, S.-P.; Wang, B.-T.; Wu, J.; Xu, Z.-Y. Eur. J. Org. Chem. 2007, 2007, 1007–1012. (24) Xu, D.-Q.; Wu, J.; Luo, S.-P.; Zhang, J.-X.; Wu, J.-Y.; Du, X.-H.; Xu, Z.-Y. Green Chem. 2009, 11, 1239–1246. Disclosure statement (25) Gao, H.X.; Han, B.X.; Han, X.; Li, J.; Jiang, T.; Liu, Z.M.; Wu, W.Z.; Chang, Y.H.; Zhang, J. Synth. Commun. 2004, 34, 3083–3089. No potential conflict of interest was reported by the authors. (26) Liang, S.; Liu, H.; Zhou, Y.; Jiang, T.; Han, B. New J. Chem. 2010, 34, 2534–2536. (27) Lombardo, M.; Easwar, S.; Pasi, F.; Trombini, C.; Dhavale, D. – Funding D. Tetrahedron. 2008, 64, 9203 9207. (28) Cole, A.C.; Jensen, J.L.; Ntai, I.; Tran, K.L.T.; Weaver, K.J.; This study was supported by The American Chemical Society Forbes, D.C.; Davis, J.H. J. Am. Chem. Soc. 2002, 124, Petroleum Research Fund [54721-UNI1]. 5924–5963.